Biological properties of ten human ovarian carcinoma cell lines: calibration in vitro against four platinum complexes

Abstract

Summary Ten human ovarian carcinoma cell lines have been studied as a potential in vitro screen for the development of novel anticancer platinum complexes. Lines have been established and developed both from solid and ascitic tumours, from pretreated and untreated patients, and are available at a range of in vitro passage numbers. The biological properties of the lines were consistent with them being human, epithelial and of ovarian carcinoma origin. Using a tritiated thymidine or leucine uptake method, and a 96 hour continuous drug exposure, the lines have been calibrated against four platinum-containing chemotherapeutic agents: cisplatin, iproplatin, carboplatin and tetraplatin. Striking differences in cytotoxicity were observed across the lines for each agent. Some lines were consistently resistant, others generally sensitive, whereas some showed clear evidence of differential sensitivity to a particular agent. Statistical analysis (Spearman rank correlation) involving the six possible pairings of drugs showed that cisplatin, iproplatin and carboplatin elicit a very similar pattern of response in these lines whereas tetraplatin elicits a completely different response pattern. Similar cytotoxicity values were obtained using a soft agar cloning assay. Results using a tetrazolium dye reduction assay, however, gave somewhat higher and more variable values, particularly with tetraplatin. The thymidine uptake assay will be adopted in further studies on a selected panel of six lines. This panel encompasses the spectra of sensitivities identified for each of the four agents against the original ten lines and may provide a useful screening facility for the development of novel platinum drugs, in that it detects both cell line-determined and structure-determined differences in cytotoxicity.Traditionally, the development of new drugs for the treatment of malignant diseases has relied predominantly on transplantable murine tumour models, such as those used by the National Cancer Institute (NCI) (Frei, 1982;Venditti, 1983). Such models include the P388 leukaemia, L1210 leukaemia, Lewis lung carcinoma, B16 melanoma, Colon 38 and CD8F1 mammary carcinoma. Our earlier work, which predicted the clinical antitumour activities of the platinum analogues JM8 (carboplatin) and JM9 (iproplatin), exploited predominantly the platinum-sensitive ADJ/PC6 murine plasmacytoma (Harrap et al., 1980;Harrap, 1985). Other workers have generated cisplatin-resistant variants of the L1210 and P388 tumours in attempts to identify novel platinum drugs which might exhibit wider spectra of antitumour activities (Burchenal et al., 1979(Burchenal et al., , 1980. Tetraplatin exhibits no cross-resistance in such models and is currently under preclinical development at NCI (Anderson et al., 1986). A recent reappraisal of screening models at the NCI has resulted in the replacement of the in vivo murine panel in favour of a range of in vitro human tumour cell lines representative of the major histological types (Boyd, 1986).Clinical trials using platinum-con...

Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines

“…Details of their establishment and biological properties have been described previously (Hills et al, 1989;Kelland et al, 1993). In addition, variants with acquired cisplatin resistance have been generated by continuously exposing cells to increasing concentrations of drug (41M/ 41McisR, CHI/CH1cisR, A2780/A2780cisR) (Behrens et al, 1987;Kelland et al, 1992).…”

In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473

“…AMD473 has been selected for phase I clinical trials in the UK, which are due to commence in 1997. Cell culture A panel of 11 parent human ovarian carcinomas (SKOV-3, OV1-P, A2780, HX/62, PXN94, CHI, 41M, OVCAR3, LK1, LK2 and PAl) and acquired cisplatin (cisR)-resistant sublines (A2780cisR, 4lMcisR, CHlcisR) were used in this study (Hills et al, 1989;Kelland et al, 1993a;Mellish et al, 1994). Cells were maintained free of Mycoplasma and were grown as monolayers in Dulbecco's Modified Eagle Medium supplemented with 10% fetal calf serum (Imperial Laboratories, Andover, UK), 2 mM L-glutamine and 0.5 ,ug ml-1 hydrocortisone in a humidified 6% carbon dioxide, 94% air atmosphere.…”

Antitumoral effect of interleukin-12-secreting fibroblasts in a mouse model of ovarian cancer: Implications for the use of ovarian cancer biopsy-derived fibroblasts as a vehicle for regional gene therapy

“…Unfortunately, it is only possible to culture ovarian cancer cells in a small percentage of cases, and almost exclusively from ascites, not from solid tumor biopsies. 27,28 We did not obtain any epithelial cell cultures from 41 solid ovarian tumor biopsies either, not even with cell culture conditions favoring epithelial cell growth. However, we have obtained fibroblast-like cell cultures from 38 (93%) of these biopsies.…”

“…However, a major obstacle to this approach in the case of human ovarian cancer is the difficulty of culturing ovarian tumor cells ex vivo from tumor biopsies, and, to a lesser extent, malignant ascites. 27, 28 We have shown that fibroblast-like cells can readily be cultured from human solid ovarian tumor biopsies, in contrast to epithelial ovarian tumor cells. The objective of our study was therefore to test the feasibility of using these fibroblasts as a vehicle for regional, intraperitoneal (i.p.)…”